Biology subjects

DiFrancesco, M. L.

Publications and source records attributed to DiFrancesco, M. L..

4 recordsLinked to original sources

bioRxiv2022

P3HT-GRAPHENE DEVICE FOR THE RESTORATION OF VISUAL PROPERTIES IN A RAT MODEL OF RETINITIS PIGMENTOSA

Retinal degeneration is one of the prevalent causes of blindness worldwide, for which no effective treatment has yet been identified. Inorganic photovoltaic devices have been investigated for visual restoration in advanced stage Retinitis pigmentosa (RP), although lack of implant flexibility and foreign-object reactions have limited their application. Organic photoactive retinal prostheses may overcome these limitations, being biomimetic and tissue friendly. Inspired by organic photovoltaic strategies involving graphene, a hybrid retinal prosthesis was recently engineered consisting of a dual poly-3-hexylthiophene (P3HT) and graphene layer onto a flexible substrate. Here, this hybrid prosthesis was subretinally implanted in vivo in 5-month-old Royal College of Surgeons (RCS) rats, a rodent model of RP. Implanted dystrophic rats restored visual performances at both subcortical and cortical levels in response to light stimuli, in the absence of marked inflammatory responses. Moreover, the analysis of the physical-mechanical properties after prolonged permanence in the eye showed excellent biocompatibility and robustness of the device. Overall, the results demonstrate that graphene-enhanced organic photovoltaic devices can be suitably employed for the rescue of retinal dystrophies and supports the translation of the organic strategy into the medical practice. TABLE OF CONTENTSInspired by organic photovoltaic, a hybrid retinal prosthesis consisting of poly-3-hexylthiophene (P3HT) and graphene on a flexible substrate was subretinally implanted in vivo in Royal College of Surgeons (RCS) rats, a model of Retinitis pigmentosa. Implanted dystrophic rats restored visual performances at both subcortical and cortical levels in response to light stimuli, in the absence of marked inflammatory responses. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=37 SRC="FIGDIR/small/507903v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1cb30a0org.highwire.dtl.DTLVardef@e57c2corg.highwire.dtl.DTLVardef@3b3c8corg.highwire.dtl.DTLVardef@10442d7_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Characterization of cardiac pacemaker activity in the primate lemur Microcebus murinus.

BackgroundGray mouse lemurs (Microcebus murinus) are the smallest and most ancestral primates known. Their size falls in between that of mice and rats, and their genetic proximity to humans makes them an emerging model to study age-related neurodegeneration. Since mouse lemurs replicate similar senescence processes of humans, they constitute a useful model for studying cardiovascular dysfunctions. However, their cardiac physiology is unknown. Thus, we investigated the cardiac pacemaker activity generated by the sinoatrial node (SAN) of mouse lemurs, presenting the first characterization of heart automaticity in nonhuman primates. Methods and ResultsWe recorded cardiac automaticity in mouse lemurs and in their SAN tissues and pacemaker myocytes. Mouse lemurs have a heart rate (HR) in between those of mice and rats and a similar generation of the SAN electrical impulse. Their SAN myocytes express the main pacemaker currents at densities similar to mice: the hyperpolarization-activated current (If) and the L-type (Ica,L) and T-type (Ica,T) calcium currents. Conversely, their ventricular depolarization resembles that of large mammals and despite the small size of mouse lemurs, the total number of heartbeats in their life corresponds to what can be attained by humans. Using muscle-derived stem cells (MDSCs) from mouse lemurs, we also differentiated pacemaker-like (PML) cells showing spontaneous automaticity and expressing markers of native SAN myocytes (HCN4 and connexin-45). ConclusionsOur characterization of heart automaticity in Microcebus murinus provides new opportunities for comparative cardio-physiology studies in primates and with humans and for testing molecules that could modulate age-related dysfunctions of heart rate.

physiology↗

bioRxiv2019

A Membrane-Targeted Photoswitch Potently Modulates Neuronal Firing

Optical technologies allowing modulation of neuronal activity at high spatio-temporal resolution are becoming paramount in neuroscience. We engineered novel light-sensitive molecules by adding polar groups to a hydrophobic backbone containing azobenzene and azepane moieties. We demonstrate that the probes stably partition into the plasma membrane, with affinity for lipid rafts, and cause thinning of the bilayer through their trans-dimerization in the dark. In neurons pulse-labeled with the compound, light induces a transient hyperpolarization followed by a delayed depolarization that triggers action potential firing. The fast hyperpolarization is attributable to a light-dependent decrease in capacitance due to membrane relaxation that follows disruption of the azobenzene dimers. The physiological effects are persistent and can be evoked in vivo after labeling the mouse somatosensory cortex. These data demonstrate the possibility to trigger neural activity in vitro and in vivo by modulating membrane capacitance, without directly affecting ion channels or local temperature.

neuroscience↗

bioRxiv2018

Bradycardic mice undergo effective heart rate improvement after specific homing to the sino-atrial node and differentiation of adult muscle derived stem cells.

Current treatments for heart automaticity disorders still lack a safe and efficient source of stem cells to restore normal biological pacemaking. Since adult Muscle-Derived Stem Cells (MDSC) show multi-lineage differentiation in vitro including into spontaneously beating cardiomyocytes, we questioned whether they could effectively differentiate into cardiac pacemakers, a specific population of cardiomyocytes producing electrical impulses in the sino-atrial node (SAN) of adult heart. We show here that beating cardiomyocytes, differentiated from MDSC in vitro, exhibit typical characteristics of cardiac pacemakers: expression of markers of the SAN lineage Hcn4, Tbx3 and Islet1, as well as spontaneous calcium transients and hyperpolarization-activated "funny" current and L-type Cav1.3 channels. Pacemaker-like myocytes differentiated in vitro from Cav1.3-deficient mouse stem cells produced slower rate of spontaneous Ca2+ transients, consistent with the reduced activity of native pacemakers in mutant mice. In vivo, undifferentiated wild type MDSC migrated and homed with increased engraftment to the SAN of bradycardic mutant Cav1.3-/- within 2-3 days after systemic I.P. injection. The increased homing of MDSCs corresponded to increased levels of the chemokine SDF1 and its receptor CXCR4 in mutant SAN tissue and was ensued by differentiation of MDSCs into Cav1.3-expressing pacemaker-like myocytes within 10 days and a significant improvement of the heart rate maintained for up to 40 days. Optical mapping and immunofluorescence analyses performed after 40 days on SAN tissue from transplanted wild type and mutant mice showed MDSCs integrated as pacemaking cells both electrically and functionally within recipient mouse SAN. These findings identify MDSCs as directly transplantable stem cells that efficiently home, differentiate and improve heart rhythm in mouse models of congenital bradycardia.

cell biology↗